Kantarjian, Hagop

Purpose Decitabine, a DNA-targeted hypomethylating agent, is approved by the United States Food and Drug Administration for treatment of patients with myelodysplastic syndromes (MDS) on a schedule of 15 mg/m2 administered via intravenous (IV) infusion every 8 hours for 3 days. This study assessed the efficacy and safety of an alternative dosing regimen administered on an outpatient basis in academic and community-based practices. Patients and Methods Patients were treated with decitabine 20 mg/m2 by IV infusion daily for 5 consecutive days every 4 weeks. Eligible patients were ≥ 18 years of age and had MDS (de novo or secondary) of any French-American-British (FAB) subtype and an International Prognostic Scoring System (IPSS) score ≥ 0.5. The primary end point was the overall response rate (ORR) by International Working Group (IWG 2006) criteria; secondary end points included cytogenetic responses, hematologic improvement (HI), response duration, survival, and safety. Results Ninety-nine patients were enrolled; the ORR was 32% (17 complete responses [CR] plus 15 marrow CRs [mCRs]), and the overall improvement rate was 51%, which included 18% HI. Similar response rates were observed in all FAB subtypes and IPSS risk categories. Among patients who improved, 82% demonstrated responses by the end of cycle 2. Among 33 patients assessable for a cytogenetic response, 17 (52%) experienced cytogenetic CR (n = 11) or partial response (n = 6). Conclusion Decitabine given on a 5-day schedule provided meaningful clinical benefit for patients with MDS, with more than half demonstrating improvement. This suggests that decitabine can be administered in an outpatient setting with comparable efficacy and safety to the United States Food and Drug Administration–approved inpatient regimen.

Abstract Purpose: Patients with hypereosinophilic syndrome (HES) or chronic eosinophilic leukemia (CEL) that are refractory to standard therapies are difficult to manage and have significantly shortened life expectancy. Experimental Design: CD52 is a surface glycoprotein highly expressed on eosinophils. We treated 11 patients with advanced HES/CEL with alemtuzumab, a humanized anti-CD52 monoclonal antibody. Alemtuzumab was administered, in general, first in escalating doses (5, 10, 30 mg i.v. on days 1-3), then at the tolerated dose thrice per week for a total of 12 doses. Patients with complete hematologic response (CHR; normal percent and absolute eosinophil count) were allowed to continue therapy once weekly as maintenance. Results: Ten patients (91%) achieved CHR after a median of 2 weeks (0.5-5 weeks) of therapy. Bone marrow eosinophilia resolved in four of seven evaluable patients. The median duration of CHR was 3 months (1.5-17+ months). Seven of the 10 CHR patients relapsed, five while off-therapy. Two patients achieved second CHR upon alemtuzumab rechallenge. Three patients experienced mild infusion-related symptoms, two developed cytomegalovirus reactivation requiring therapy, and one developed orbital lymphoma that was successfully treated. Conclusions: Our limited experience suggests alemtuzumab to be a valuable therapy for advanced HES or CEL, refractory to standard therapies, and supports the clinical evaluation of alemtuzumab in a larger trial.

Abstract Purpose: Molecular characterization of Philadelphia chromosome–negative (Ph−) chronic myeloproliferative disorders, such as systemic mastocytosis (SM), has provided a clear rationale for investigating novel targeted therapies. The tyrosine kinase (TK) inhibitor dasatinib is 325-fold more potent against Bcr-Abl TK than imatinib in vitro, significantly inhibiting wild-type KIT and platelet-derived growth factor receptor β TKs, and is active against cells carrying the mutant KIT-D816V gene. Experimental Design: In this phase 2, open-label study, the efficacy of dasatinib (140 mg/d) was investigated in 67 patients with various Ph− myeloid disorders, including SM (n = 33; 28 KIT-D816V positive). Results: The overall response rate to dasatinib in patients with SM was 33%. Only two patients, one with SM-myelofibrosis and one with SM-chronic eosinophilic leukemia, achieved complete response (elimination of mastocytosis) lasting for 5 and 16 months, respectively. Both patients were negative for KIT-D816V mutation, had low tryptase levels, abnormal WBC counts, and anemia, and had failed prior therapy with erythropoietin. Additional nine SM patients had symptomatic response, lasting 3 to 18+ months. Complete responses were achieved in two other patients (acute myeloid leukemia and hypereosinophilic syndrome). No responses were observed among patients with myelodysplastic syndromes and primary myelofibrosis. The majority of adverse events were grade 1/2. Conclusion: These data show that dasatinib therapy may benefit a selected group of SM patients, primarily by improving their symptoms, but it does not eliminate the disease in the patients with KIT-D816V mutation.

Abstract Nilotinib, an orally bioavailable, selective Bcr-Abl tyrosine kinase inhibitor, is 30-fold more potent than imatinib in pre-clinical models, and overcomes most imatinib resistant BCR-ABL mutations. In this phase 2 open-label study, 400 mg nilotinib was administered orally twice daily to 280 patients with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) after imatinib failure or intolerance. Patients had at least 6 months of follow-up and were evaluated for hematologic and cytogenetic responses, as well as for safety and overall survival. At 6 months, the rate of major cytogenetic response (Ph ≤ 35%) was 48%: complete (Ph = 0%) in 31%, and partial (Ph = 1%-35%) in 16%. The estimated survival at 12 months was 95%. Nilotinib was effective in patients harboring BCR-ABL mutations associated with imatinib resistance (except T315I), and also in patients with a resistance mechanism independent of BCR-ABL mutations. Adverse events were mostly mild to moderate, and there was minimal cross-intolerance with imatinib. Grades 3 to 4 neutropenia and thrombocytopenia were observed in 29% of patients; pleural or pericardial effusions were observed in 1% (none were severe). In summary, nilotinib is highly active and safe in patients with CML-CP after imatinib failure or intolerance. This clinical trial is registered at http://clinicaltrials.gov as ID no. NCT00109707.

Abstract Gain-of-function mutations of the receptor tyrosine kinase KIT play a key role in the pathogenesis of systemic mastocytosis (SM), gastrointestinal stromal tumors (GISTs), and some cases of acute myeloid leukemia (AML). Whereas KIT juxtamembrane domain mutations seen in most patients with GIST are highly sensitive to imatinib, the kinase activation loop mutant D816V, frequently encountered in SM, hampers the binding ability of imatinib. We investigated the inhibitory activity of the novel tyrosine kinase inhibitor EXEL-0862 against 2 subclones of human mast cell line-1 (HMC-1)—HMC-1.1, harboring the juxtamembrane domain mutation V560G, and HMC-1.2, carrying V560G and the activation loop mutation D816V, found in more than 80% of patients with SM. EXEL-0862 inhibited the phosphorylation of KIT in a dose-dependent manner and decreased cell proliferation in both mast cell lines with higher activity against HMC-1.2 cells. The phosphorylation of KIT-dependent signal transducer and activator of transcription-3 (STAT3) and STAT5 was abrogated upon exposure to nanomolar concentrations of EXEL-0862. In addition, EXEL-0862 induced a time- and dose-dependent proapoptotic effect in both mast cell lines and caused a significant reduction in mast-cell content in bone marrow samples from patients with SM harboring D816V and from those without the D816V mutation. We conclude that EXEL-0862 is active against KIT activation loop mutants and is a promising candidate for the treatment of patients with SM and other KIT-driven malignancies harboring active site mutations.

AbstractWe present results of 2 similarly designed but separate phase 2 studies involving single-agent lenalidomide (CC-5013, Revlimid) in a total of 68 patients with symptomatic myelofibrosis with myeloid metaplasia (MMM). Protocol treatment consisted of oral lenalidomide at 10 mg/d (5 mg/d if baseline platelet count < 100 × 109/L) for 3 to 4 months with a plan to continue treatment for either 3 or 24 additional months, in case of response. Overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia. Response in anemia was deemed impressive in 8 patients whose hemoglobin level normalized from a baseline of either transfusion dependency or hemoglobin level lower than 100 g/L. Additional treatment effects in these patients included resolution of leukoerythroblastosis (4 patients), a decrease in medullary fibrosis and angiogenesis (2 patients), and del(5)(q13q33) cytogenetic remission accompanied by a reduction in JAK2V617F mutation burden (1 patient). Grade 3 or 4 adverse events included neutropenia (31%) and thrombocytopenia (19%). We conclude that lenalidomide engenders an intriguing treatment activity in a subset of patients with MMM that includes an unprecedented effect on peripheral blood and bone marrow abnormalities.